Aberrant Myc expression causes mammary cancer. Myc is deregulated in most mammary tumors by multiple mechanisms, including gene amplification, or aberrant expression due to alterations in signaling pathways that influence Myc RNA or protein levels as well as its transcriptional activity. Each of the indicated proteins or pathways impacts on Myc expression or activity in mammary cancer. Specifically, the Notch and Wnt pathway effectors, Notch intracellular domain/C promoter-binding factor 1 and β-catenin/T-cell factor, respectively, as well as estrogen receptor alpha (ERα), bind the Myc promoter, thereby stimulating transcription. Dysregulation of transforming growth factor beta (TGFβ) and Brca1 in mammary cancer has been reviewed recently [34]. TGFβ, via Smads, suppresses Myc expression, while Brca1, which is frequently deregulated in ERα-negative, basal-like breast cancer, normally blocks Myc transcriptional activity. The ubiquitin-specific protease ubiquitin-specific protease 28 (USP28) was found overexpressed in breast tumors [38] and stabilizes Myc via antagonizing F-box and WB repeat domain containing 7 (FBW7), which is frequently lost or mutated in breast tumors [37]. Finally, ErbB2 activation, which is also regulated by ERα, stimulates pathways like rat sarcoma/extracellular signal-related kinase (Ras/Erk) and phosphoinositide 3-kinase/serine/threonine kinase Akt (PI3K/Akt) that influence Myc RNA and protein levels. See text for further details. Myc is an activator of RNA polymerase II-driven transcription for multiple target genes [2] and also affects RNA polymerase I- and III-mediated transcription, thus regulating ribosome biogenesis and translation. In cancer cells, the outcome of deregulated Myc will be wide-ranging considering that Myc influences the cell cycle, protein synthesis, cell growth and metabolism, cell death, genomic instability, tumor-induced angiogenesis, adhesion, as well as other cellular functions. This is exemplified by examining the effects of Myc knockdown in breast cancer cell lines, where a genomic and phenotypic analysis revealed that selectively regulated target genes in each cell line were responsible for the differential effects resulting from Myc loss [40].

Ins and outs of the 'black box' MYC during normal mammary gland development. The diagram displays the models (italic, top) used to investigate the various inputs and outputs of Myc (green boxes). Speculations based on other model systems that have not yet been shown in the mammary gland are presented in red. Inputs are signaling molecules that are known or suggested to impact on Myc levels; inputs are not applicable (n.a.) in transgenic models with genetically deregulated Myc levels. The outputs are, where available, direct targets of Myc transcriptional activity and general biological functions described for Myc at the specific developmental stage (italic, bottom). During embryogenesis, transgenic expression of Neuregulin3 (Nrg3), a major factor controlling mammary placode development, induced high Myc levels, thereby changing the proliferative and adhesive properties of cells [11]. The speculated role of Myc in mammary stem cells (SCs) is mostly based on data from hematopoietic SCs and the known importance of Wnt and Notch pathways in other SC types [13]. Myc's role during puberty and early pregnancy has not yet been analyzed, but as various steroids and paracrine factors can induce its expression [3] Myc might play a role in promoting proliferation and cell growth via its numerous cell cycle and translation-related targets. A transgenic mouse model (MMTV-rtTA/TetO-MYC (MTB/TOM)) revealed that Myc overexpression during late pregnancy leads to precocious proliferation and differentiation via repression of Caveolin1 (Cav1) and signal transducer and activator of transcription (Stat) 5 hyperactivation [27]. Despite its low levels during lactation, Myc has an important role in mRNA translation, as shown in our own laboratory using mammary glands conditionally lacking Myc (Myc-CKO) [29]. Finally, in Socs3 conditional knockout (CKO) mice it was shown that increased Stat3 activation leads to accelerated apoptosis via high levels of Myc, suggesting a direct role for Myc downstream of Stat3 in involution [31]. More detailed discussion can be found in the text. K14, Keratin14; KO, knockout; N-Cad, N-cadherin.